The present invention relates to an improving agent for hypoalbuminaemia containing a hydantoin derivative or a pharmaceutically acceptable salt thereof as an effective ingredient.
The concentration of serum albumin is 3.5-5.5 g/dL in healthy subjects. When the concentration is lowered to less than 3.5 g/dL, such condition is diagnosed as hypoalbuminaemia. Serious hypoalbuminaemia with less than 3.0 g/dL of serum albumin concentration is clinically significant. Hypoalbuminaemia causes symptoms such as edema and ascites, and worsens disorders by hyperbilirubinemia. This disease occurs from various causes such as a decrease in albumin synthesis, loss of albumin from blood and dilution of plasma. Albumin is synthesized only by hepatocytes and a decrease in their synthesis causes hypoalbuminaemia. The main causes of a decrease in the synthesis of albumin are a deficiency of amino acid supply by nutrition disorders and a lowered ability for albumin synthesis by hepatic disease. The loss of albumin from blood is caused by renal failure such as nephritic syndrome, traumatic injury such as burn and protein-losing gastroenteropathy. Dilution of plasma owing to heart failure, accelerated catabolism by hyperthyroidism and the like also cause hypoalbuminaemia. As a remedy for hypoalbuminaemia, dietetic therapy using a high protein diet and drug therapy by total amino acid preparations have been performed. However, in the case of intravenous administration of amino acids, caution is needed against an exhibition of side effects such as acid-base balance disorder, hyperammonaemia, imbalance of amino acids and azotemia. Also, when blood protein preparations are used, there are characteristic problems with such preparations such as contamination with virus.
As mentioned above, amino acid preparations and blood preparations for intravenous administration are mainly used at present as a therapeutic drug for hypoalbuminaemia. There is a strong demand in the clinical field for a therapeutic agent having higher safety and which can be orally administrated.
Several hydantoin compounds of the present invention were found as novel substances having plant growth controlling action. As a result of investigations thereafter for the compounds including analogs thereof, they have been found to have pharmacological actions such as hypoglycemic and hypolipemic actions, and also exhibit low toxicity resulting in almost no side effects. See U.S. Pat. Nos. 4,647,574 and 4,683,240, each to Ienaga et al, and Japanese Laid-Open Patent Publications Sho-57/114578, Sho-60/188373, Sho-61/122275, Sho-62/45525, Sho-62/14, Hei-01/75473, Hei-01/299276, etc.). It has been also disclosed that the compounds of the present invention are useful as: 1) agents for lowering uremic toxin (Japanese Laid-Open Patent Publication Hei-03/72463), 2) eliminating agents of active oxygen and free radicals (Japanese Laid-Open Patent Publication Hei-09/227377), and 3) therapeutic agents for intractable vasculitis (Japanese Laid-Open Patent Publication 2000/212083 and U.S. Pat. No. 6,251,929 B1). However, the therapeutic effect of the compounds of the present invention for hypoalbuminaemia has not ever been found.
The present inventors have carried out intensive investigations and have found that the hydantoin derivatives of the present invention have a therapeutic effect for hypoalbuminaemia whereupon the present invention has been accomplished. The compounds of the present invention are less toxic and have almost no side effect, and accordingly they are quite useful as an improving agent for hypoalbuminaemia having higher safety and are capable of oral administration.
The present invention solves the above-mentioned problems and provides a highly safe therapeutic agent for hypoalbuminaemia which can be oral administration.
The hydantoin derivatives and their pharmaceutically acceptable salts of the present invention may be us ed as therapeutic agents for the treatment of hypoalbuminaemia in patients known to be in need of such treatment. In embodiments of the present invention patients may be treated for hypoalbuminaemia caused by: 1) a deficiency of amino acid supply caused by nutrition disorders, 2) a lowered ability for albumin synthesis due to hepatic disease, 3) loss of albumin from blood due to renal failure such as nephritic syndrome, 4) traumatic injury such as burn, 5) protein-losing gastroenteropathy, 6) dilution of plasma owing to heart failure, and 7) accelerated catabolism by hyperthyroidism, and the like.
The pharmaceutical compositions employed in the present invention include at least one hydantoin derivative represented by the general formula (I) or pharmaceutically acceptable salts of the derivatives represented by the general formula (I): 
wherein each of R1 and R2, which may be the same or different, is hydrogen, an alkyl group or a cycloalkyl group; and each of X and Y, which may be the same or different, is hydrogen, a hydroxyl group, an alkyl group or an alkoxy group, or X and Y together represent an oxo group.
The hydantoin derivatives and their pharmaceutically acceptable salts may be administered orally or parenterally to patients in need of treatment in pharmaceutically effective amounts with little, if any side effects, low toxicity, and high safety to substantially increase serum albumin levels or values in patients diagnosed with hypoalbuminaemia.
The effective ingredient of the improving agent for hypoalbuminaemia according to the present invention is a hydantoin derivative represented by the following formula (I) or a pharmaceutically acceptable salt thereof: 
wherein each of R1 and R2, which may be the same or different, represents hydrogen, an alkyl group or a cycloalkyl group; and each of X and Y, which may be the same or different, represents hydrogen, a hydroxyl group, an alkyl group or an alkoxy group, or X and Y together represent an oxo group.
In the above mentioned formula (I), each of R1 and R2, which may be the same or different, represents hydrogen, an alkyl group, preferably a straight or branched alkyl group having 1 to 20 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, t-pentyl, hexyl, dimethylbutyl, heptyl, octyl, nonyl, decyl or stearyl; or a cycloalkyl group, preferably a cycloalkyl group having 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
Each of X and Y, which may be the same or different, represents hydrogen, a hydroxyl group, an alkyl group, preferably a straight or branched alkyl group having 1 to 3 carbon atoms such as methyl, ethyl, propyl, isopropyl; or an alkoxy group, preferably a straight or branched alkoxy group having 1 to 5 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, t-butoxy, pentoxy, isopentoxy, neopentoxy; or X and Y together represent an oxo group.
Preferred compounds of the present invention are:
[Compound 1] Hydantoin
[Compound 2] 1-Methylhydantoin
[Compound 3] 3-Methylhydantoin
[Compound 4] 1-Ethylhydantoin
[Compound 5] 1-Propylhydantoin
[Compound 6] 1-Butylhydantoin
[Compound 7] 1-t-Butylhydantoin
[Compound 8] 1-Hexylhydantoin
[Compound 9] 1-(1,3-Dimethylbutyl)hydantoin
[Compound 10] 1-Decylhydantoin
[Compound 11] 1-Stearylhydantoin
[Compound 12] 1,3-Dimethylhydantoin
[Compound 13] 1,5-Dimethylhydantoin
[Compound 14] 3,5-Dimethylhydantoin
[Compound 15] 1-Cyclopentylhydantoin
[Compound 16] 1-Cyclohexylhydantoin
[Compound 17] 1-Cyclohexyl-3-methylhydantoin
[Compound 18] 3-Cyclohexylhydantoin
[Compound 19] 1,3-Dicyclohexylhydantoin
[Compound 20] 5-Hydroxyhydantoin
[Compound 21] 5-Hydroxy-1-methylhydantoin
[Compound 22] 5-Hydroxy-3-methylhydantoin
[Compound 23] 5-Hydroxy-1-ethylhydantoin
[Compound 24] 5-Hydroxy-1-propylhydantoin
[Compound 25] 5-Hydroxy-1-butylhydantoin
[Compound 26] 5-Hydroxy-1-t-butylhydantoin
[Compound 27] 5-Hydroxy-1-hexylhydantoin
[Compound 28] 5-Hydroxy-1-(1,3-dimethylbutyl)hydantoin
[Compound 29] 5-Hydroxy-1-decylhydantoin
[Compound 30] 5-Hydroxy-1-stearylhydantoin
[Compound 31] 5-Hydroxy-1-cyclopentylhydantoin
[Compound 32] 5-Hydroxy-1-cyclohexylhydantoin
[Compound 33] 5-Hydroxy-1-cyclohexyl-3-methylhydantoin
[Compound 34] 5-Hydroxy-1,3-dimethylhydantoin
[Compound 35] 5-Hydroxy-1,5-dimethylhydantoin
[Compound 36] 5-Hydroxy-3,5-dimethylhydantoin
[Compound 37] 5-Hydroxy- 1,3-dicyclohexylhydantoin
[Compound 38] 5-Methoxyhydantoin
[Compound 39] 5-Methoxy-1-methylhydantoin
[Compound 40] 5-Methoxy-3-methylhydantoin
[Compound 41] 5-Methoxy-1-ethylhydantoin
[Compound 42] 5-Methoxy-1-propylhydantoin
[Compound 43] 5-Methoxy-1-butylhydantoin
[Compound 44] 5-Methoxy-1-cyclohexylhydantoin
[Compound 45] 5-Methoxy-3-cyclohexylhydantoin
[Compound 46] 5-Ethoxyhydantoin
[Compound 47] 5-Ethoxy-1-methylhydantoin
[Compound 48] 5-Ethoxy-3-methylhydantoin
[Compound 49] 5-Ethoxy-1-ethylhydantoin
[Compound 50] 5-Ethoxy-1-propylhydantoin
[Compound 51] 5-Ethoxy-1-butylhydantoin
[Compound 52] 5-Propoxyhydantoin
[Compound 53] 5-Propoxy-1-methylhydantoin
[Compound 54] 5-Propoxy-3-methylhydantoin
[Compound 55] 5-Propoxy-1-ethylhydantoin
[Compound 56] 5-Propoxy-1-propylhydantoin
[Compound 57] 5-Propoxy-1-butylhydantoin
[Compound 58] 5-Butoxyhydantoin
[Compound 59] 5-Butoxy-1-methylhydantoin
[Compound 60] 5-Butoxy-3-methylhydantoin
[Compound 61] 5-t-Butoxyhydantoin
[Compound 62] 5-t-Butoxy-1-methylhydantoin
[Compound 63] 5-t-Butoxy-3-butylhydantoin
[Compound 64] Imidazolidinetrione
[Compound 65] 1-Methylimidazolidinetrione
[Compound 66] 1-Ethylimidazolidinetrione
[Compound 67] 1-Butylimidazolidinetrione
[Compound 68] 1-Isobutylimidazolidinetrione
[Compound 69] 1-t-Butylimidazolidinetrione
[Compound 70] 1-Hexylimidazolidinetrione
[Compound 71] 1-(1,3-Dimethylbutyl)imidazolidinetrione
[Compound 72] 1-Decylimidazolidinetrione
[Compound 73] 1-Cyclopentylimidazolidinetrione
[Compound 74] 1-Cyclopentyl-3-ethylimidazolidinetrione
[Compound 75] 1-Cyclohexylimidazolidinetrione
[Compound 76] 1,3-Dimethylimidazolidinetrione
[Compound 77] 1,3-Dicyclohexylimidazolidinetrione
The hydantoin derivatives of the present invention include the pharmaceutically acceptable salts of the compounds represented by the above given formula (I). Exemplary salts of the present invention are acid addition salts of the hydantoin derivatives of general formula (I) with hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, perchloric acid, thiocyanic acid, boric acid, formic acid, acetic acid, haloacetic acid, propionic acid, glycolic acid, citric acid, tartaric acid, succinic acid, gluconic acid, lactic acid, malonic acid, fumaric acid, anthranilic acid, benzoic acid, cinnamic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, or sulfanilic acid. Other salts of the present invention include salts of the hydantoin derivatives of general formula (I) with: a) an alkali metal such as sodium and potassium, b) an alkaline-earth metal such as calcium, magnesium and barium, and c) other metals such as aluminum and zinc.
The pharmaceutically acceptable salts may be manufactured by conventional methods, starting from the hydantoin derivatives of the present invention in a free state or free form, or by conversion from one salt to another salt.
When there are steric isomers or stereoisomers such as cis-trans isomers, optical isomers, or conformational isomers, hydrates or complexes for the compounds of the present invention, the present invention includes any and all of such isomers, hydrates and complexes.
The compounds of the present invention may be manufactured by conventional methods as disclosed, for example, in Japanese Laid Open (Kokai) Nos. 61/122275 (published Jun. 10, 1986) and 62/14 (published Jan. 6, 1987) and their corresponding U.S. Pat. Nos. 4,647,574 and 4,683,240 each to Ienaga et al, respectively. The disclosures of each of said Japanese publications and U.S. Pat. Nos. 4,647,574 and 4,683,240 are herein incorporated by reference in their entireties. For example, hydantoin derivatives of the present invention may be produced by methods as disclosed in U.S. Pat. No. 4,647,574 at column 2 line 39 to column 3 line 32. Thus, the hydantoin derivatives may be produced by first conventionally esterifying a glyoxylic acid. For example, a glyoxylic acid is reacted with an alcohol or 2-methoxyethanol, at room temperature or at a suitable temperature above room temperature or under reflux, for about several hours to about a day, with the produced water being removed, in the presence of an organic acid catalyst such as p-toluene-sulfonic acid or camphorsulfonic acid in an aprotic solvent such as benzene, toluene, xylene or carbon tetrachloride. Then the produced glyoxylic acid ester or an o-alkylglyoxylic acid ester (glyoxylic acid ester alcoholate) is, without being isolated or further purified, reacted at room temperature or heated under reflux for about 1 hour to about several days with, e.g., N-alkylurea, N-cycloalkylurea, N,Nxe2x80x2dialkylurea or N,Nxe2x80x2-dicycloalkylurea in an appropriate solvent such as water, acetic acid or alcohol, such as butanol or mixtures thereof, to give compounds of the present invention represented by the general formula (I).
The above-mentioned reaction can also be carried out with an xcex1-ketocarbonic acid such as pyruvic acid as the starting material instead of a glyoxylic acid.
The compounds of the present invention wherein X or Y is an alkoxy group may be produced from a hydantoin derivative as prepared, e.g., by the process described above, by a conventional O-alkylation process. The hydantoin derivatives may be reacted with p-toluenesulfonyl chloride or mesyl chloride to introduce a removable residue into the hydroxy group at the 5-position, in the presence of an organic base such as a lower alkylamine or an alkali metal alkoxide in an appropriate solvent which does not inhibit the reaction. During or after the reaction, the resultant product is reacted with the alcohol corresponding to the X or Y substituent of the desired hydantoin derivative to give the compound of the present invention. This O-alkylation may be carried out at room temperature or at a suitable temperature above room temperature or under reflux, for about several hours to about several days.
The compounds of the present invention also include products from the N-alkylation of the hydantoin derivatives. The hydantoin derivative is reacted with a halogenated alkyl, a halogenated cycloalkyl, a dialkylsulfuric acid such as dimethylsulfonic acid, a p-toluenesulfonic acid alkyl ester or a p-toluenesulfonic acid cycloalkyl ester, in the presence of a base such as a lower alkyl amine, an alkali metal alkoxide or a hydroxyalkyl metal in an appropriate solvent which does not inhibit the reaction such as absolute alcohol, or dimethyl sulfoxide. The N-alkylation may be carried out at room temperature or at a suitable temperature above room temperature for about several hours to about several days.
When X and Y represent an oxo group, the hydantoin derivatives or imidazolidinetrione derivatives of the present invention may be produced by methods as disclosed in T. Yonezawa et al, Nippon Kagaku Zasshi, 89, No. 8, pp 62-64 (1968), Tad L. Patton, J. Org. Chem., 32, No. 2, 383-388 (1967), and U.S. Pat. No. 4,683,240 at column 3 lines 27-49. For example, as disclosed in U.S. Pat. No. 4,683,240, oxalyl chloride and an N-substituted urea, such as an N-alkylurea, or N-cycloalkylurea may be stirred in an appropriate solvent such as tetrahydrofuran which does not inhibit the reaction in an ice-water bath or at room temperature. Alternatively, diethyl oxalate and the above-mentioned N-substituted urea may be stirred in an appropriate solvent which does not inhibit the reaction in the presence of an organic base such as an amine or alkali metal alkoxide at room temperature, if desired, by heating to higher temperatures to give the imidazolidinetrione derivatives of the present invention.
The compounds of the invention can also be prepared by conventional N-alkylation wherein unsubstituted, 1-alkylsubstituted or 1-cycloalkylsubstituted imidazolidinetrione is reacted with halogenated alkyl.
The compounds of the present invention prepared as described above may be purified by conventional methods such as distillation, chromatography and recrystallization. The compounds may be identified by means of, for example, elementary analysis, melting point measurement, infrared (IR), nuclear magnetic resonance (NMR), ultraviolet (UV), and mass spectroscopy (MS).
The compounds of the present invention, which include the hydantoin derivatives and their pharmaceutically acceptable salts and complexes, can be made into pharmaceutical preparations by combining one or more of the compounds with at least one pharmaceutically acceptable carrier or diluent. Any of the known methods for providing preparations, such as for oral administrations (e.g. tablets, capsules, powders, liquids, etc.) and for parenteral administrations (e.g. for subcutaneous, intravenous, intramuscular, intrarectal and intranasal administrations) may be used to produce the pharmaceutical compositions of the present invention. In preparing the preparations, the hydantoin derivatives of the present invention may be used in the form of their pharmaceutically acceptable salts. The compounds of the present invention may be used either solely or jointly in pharmaceutically effective amounts for treating animals or humans. The compounds of the invention can be used either solely or jointly together in pharmaceutically acceptable amounts with pharmaceutically effective amounts of other pharmaceutically active components in pharmaceutical compositions or preparations.
In the case of preparations for oral administration, one or more of the compounds of the present invention either alone or in combination with commonly-used pharmaceutically acceptable excipients in pharmaceutically acceptable amounts such as at least one suitable pharmaceutically acceptable additive or carrier (e.g. lactose, mannitol, corn starch, potato starch, potassium citrate, etc.) may be mixed with one or more pharmaceutically acceptable: (1) binders such as cellulose derivatives (e.g. crystalline cellulose, hydroxypropylcellulose, etc.), gum arabicum, corn starch, gelatin, etc., (2) disintegrating agents such as corn starch, potato starch, calcium carboxymethylcellulose, etc., (3) lubricating agents such as talc, magnesium stearate, etc. and (4) other pharmaceutically acceptable excipients including pharmaceutically acceptable bulking agents, moisturizing agents, buffers, preservatives, perfumes and the like to obtain tablets, diluted powders, granules or capsules.
In the case of injections, it is possible to prepare solutions or suspensions of one or more compounds of the present invention in pharmaceutically acceptable carriers such as an aqueous or nonaqueous solvent. Examples of solvents which may be used are distilled water for injection, physiological saline solution, Ringer""s solution, plant oil, synthetic fatty acid glycerides, higher fatty acid esters, propylene glycol, etc.
It is also possible, depending upon the type of the disease, to prepare pharmaceutical preparations other than the above-mentioned ones which are suitable for therapy depending upon the state of the patient. Exemplary of other pharmaceutical preparations are syrups, suppositories, inhalations, aerosol preparations, collyriums, medicines for external use (e.g. ointments, gels, poultices), etc.
The preferred dosage of the compound of the present invention varies depending upon the subject to be administered (age, body weight, symptoms, etc. of the patient), form of the preparation, method for the administration, term for the administration, etc. To achieve the desired result, the compound may be usually administered by the oral route with a daily dose of 1-1,000 mg per day, preferably 5-600 mg per day, to common adults. In the case of a parenteral administration such as by injection, the preferred dosage, may be from ⅓ to {fraction (1/10)} of the above-mentioned oral dosages because of the effects of absorption, etc. in the oral route.
Preferred embodiments of the improving agent for hypoalbuminaemia of the present invention containing the compound represented by the above formula (I) are:
(1) A improving agent for hypoalbuminaemia containing the compound represented by the formula (I) wherein one of X and Y represents hydrogen as an active ingredient.
(2) An agent according to the above subparagraph (1) wherein the other of X and Y represents a hydroxyl group.
(3) An agent according to the above subparagraph (2) wherein one of R1 and R2 represents an alkyl group and the other represents hydrogen.
(4) An agent according to the above subparagraph (3) wherein R1 represents an alkyl group.
(5) An agent according to the above subparagraph (4) wherein R1 represents an alkyl group having 1 to 4 carbon atoms.
(6) An agent according to the above subparagraph (5) wherein R1 represents methyl.
(7) An agent according to one of the above subparagraphs (1)-(6) which is used for the therapy of hypoalbuminaemia owing to hepatic disease.
(8) An agent according to one of the above subparagraphs (1)-(6) which is used for the therapy of hypoalbuminaemia owing to nutrition disorders.
(9) An agent according to one of the above subparagraphs (1)-(6) which is used for the therapy of hypoalbuminaemia owing to renal failure.
(10) An agent according to one of the above subparagraphs (1)-(6) which is used for the therapy of hypoalbuminaemia owing to traumatic injury.
(11) An agent according to one of the above subparagraphs (1)-(6) which is used for the therapy of hypoalbuminaemia owing to protein- losing gastroenteropathy.
(12) An agent according to one of the above subparagraphs (1)-(6) which is used for the therapy of hypoalbuminaemia owing to heart failure.
(13) An agent according to one of the above subparagraphs (1)-(6) which is used for the therapy of hypoalbuminaemia owing to hypercatabolism.
The most preferred compound for use in the present invention, which has been clinically confirmed as having low toxicity and lower side effects is 5-hydroxy-1-methylhydantoin (Compound 21).
The present invention is illustrated by the following non-limiting example wherein all parts, percentages and ratios are by weight, unless indicated to the contrary: